Oral pharmaceutical products prepared with carboxymethyl benzyl dextran having a low carboxymethyl d. s. of 0.15



United States Patent GRAL PHARMACEUTICAL PRODUCTS PREiARED V /1TH @ARBGXYMETHYL BENZYL DEXTRAN HAVENG A LOW CARBOXYMETHYL 115. OF 0.15

Leo J. Novak, Union, NJ assignor to The Central Pharmacal Company, Seymour, Ind. No Drawing. Filed Sept. 14, 1%2, Ser. No. 223,$41 2 (Iiaims. (Si. 167-32} This invention relates to delayed release medicaments, and to methods of production thereof, and more particularly to delayed release medicaments prepared with carboxyrnethyl benzyl dextran.

This application is a continuation-in-part of application Serial No. 835,189, filed August 21, 1959, now US. Patent No. 3,063,905.

For numerous purposes it is necessary to administer medicaments over extended periods of time in order to accomplish the desired result. In most cases it is necessary to administer the medicament at stated intervals in order to maintain a useful concentration of the medicament in the body Without at the same time having present toxic amounts. t is Well known that almost any medicament will produce harmful instead of beneficial results when excessive quantities are introduced into the blood stream of the body, and that too small quantities produce little, if any, beneficial effect, and may even prove harmful in establishing immunity against the medicament. It is accordingly necessary to exercise extreme care in the administration of all medicaments, and in particular those of a high degree of toxicity.

The necessity of maintaining a regulated level of a medicament in the blood stream has in the past made it essential to administer regulated amounts of the medicament at fairly frequent regulated intervals, the amounts and time intervals being dependent upon the particular medicament. In cases Where the medicament has a high degree of toxicity or where the rate of excretion from the body is high it has been necessary to administer the drug at quite frequent intervals with resultant inconvenience and cost to the patient, as Well as to the physician or nurse.

It is an object or this invention to provide a practical economical means of admi istering medicaments in a manner so that the required levels of the medicament can be maintained in the body without harm to the patient and Without the necessity for frequent dosages of the medicament. This is accomplished by administering the medicament in combination with carboxymethyl benzyl dextran, and particularly carboxymethyl benzyl dextran of the character described below. By suitably regulating the composition as hereinafter described it is possible to regulate the rate of release of the medicament as desired so that much less frequent dosages are required in order to maintain a particular desired effective concentration of the medicament in the body of the patient being treated. Large dosages of the carboxymethyl benzyl dextran-medicament composition are administered at extended periods and by regulating the amount of the medicament or the type of the carboxymethyl benzyl dextran used, or both, the medicament will be released in the body to give the particular desired concentration over a particular desired period of time.

The term dextran is applied to a class of polymers of glucose having chain-like structures and usually of very high molecular weight, produced by fermentation. The structure of dextran varies somewhat depending upon its method of production. For use in preparing carboxymethyl benzyl dextran suitable for delayed release medicament compositions dextran having a ratio of repeating alpha-1,6 to alpha non-1,6 glycosidic links from 2:1 to 32:1 has been found to be particularly suitable.

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The dextran used to produce synthetic blood-volume expanders falls within this range and has a ratio of repeating alpha-1,6 to alpha non-1,6 glycosidic links of 19:1.

The molecular Weight of the dextran used in making carboxyrnethyl benzyl dextran for delayed release medicaments should fall preferably within the range of three million to sixty million, determined by light scattering which is the average molecular weight range for most of the dextrans obtained by normal fermentations. In general, the rate of release of the medicament from the carboxymethyl benzyl dextran-medicament composition is increased as the molecular Weight is reduced. Where it is desired to speed up the rate of release this can be accomplished by hydrolysis of the native dextran controlled so as to give dextran of any particular molecular weight range.

The degree of substitution of the benzyl in the carboxymethyl benxyl dextran also has an important bearing on the rate of release of the medicament from the carboxymethyl benzyl dextranmedicament compositions. In general, the rate of release is decreased as the degree of substitution is raised and lowered as the degree of substitution is increased. For most uses, a degree of substitution ranging from 0.5 to 1.5 has been found to be most desirable, a 13.5. below 0.5 giving too rapid release for most practical purposes, and above 1.5 not giving fast enough release. For some purposes, however, carboxymethyl benzyl dextran having a D5. of benzyl outide of this range is useful.

A carboxymethyl benzyl dextran, designed to give gradual release of a medicament in the body over a period of eight to sixteen hours, should have a molecular Weight ranging from three million to sixty million, a ratio of repeating alpha-1,6 to alpha non-1,6 glycosidic links of 2:1 to 32:1, and preferably 19:1, and in which the replaceable hydrogens on the hydroxyl groups have been replaced by benzyl groups to give a D8. of 0.1-1.5 and in which the D8. of the carboxymethyl is not substantially in excess of 0.15.

The mechanism of the combination of the carboxymethyl benzyl dextran and medicament is not definitely known. It is believed, however, that the medicament is held in suspension within the tightly coiled molecules of the carboxymethyl benzyl dextran. Any medicament which can be suspended in the carboxymethyl benzyl dextran Without substantial loss through decomposition, vaporization or sublimation during the processing and subsequent storage can be used with the carboxymethyl benzyl dextran and administered as a delayed release medicament, the only limitation being that the medicament selected be such that it can be homogeneously suspended in the carboxymethyl benzyl dextran and entrapped Within its coiled molecules.

Analgesics and antiarthritics such as acetophenetidin with aspirin and catiein and meperidine; antiacids and antidiarrhetics such as magnesium trisilicate; antbioiotics such as penicillin, tetracyclines, chloramphenicol, erythromycin; anticholinergics such as atropine-phenobarbital; antihistaminics such as chlorprophenyridamine, promethazine; cardiotonics such as pentaerythritol tetranitrate; diuretics such as acetazoleamide; psychopharmacological drugs such as chlorpromazine, dextroamphetamine, meprobamate; steroid hormones such as estrogens, hydrocortisoue; vasoconstrictors such as phenylephrine; vitamin preparations such as B1 etc. represent examples of medicaments which can be used with the carboxymethyl benzyl dextran in the formulation of delayed release medicaments.

The amount of medicament combined with the carboxymethyl benzyl dextran depends to a considerable degree on the desired dosage of the medicament and the influence of the concentration of the medicament on its rate of release from the combination. In the case of dextroamphetamine to 15% of the medicament in the combination has been found satisfactory. Larger amounts may, of course, be used unless the character of the medicament is such that the amount released at any time might be hazardous to the patient. In such cases, however, the benzyl D.S. may be increased so as to slow up the rate of release. This illustrates one of the principal advantages of the use of carboxymethyl benzyl dextran in delayed release medicaments, namely, that the carboxymethyl benzyl dextran can be tailor-made to fit the particular medicament and the particular type of treatment required for best results. In other Words, by selecting the particular medicament, the concentrations thereof used, and the particular benzyl D.S. a delayed release medicament can be prepared to fit any usual requirement.

The medicament can be incorporated with the carboxymethyl benzyl dextran in any suitable manner which will assure homogeneity and entrapment within the carboxymethyl benzyl dextran molecules. One convenient method of doing this has been by preparing a fluid paste of the carboxymethyl benzyl dextran in methanol using the minimum quantity of methanolone to three parts of methanol by weight to one part of carboxymethyl benzyl dextran. The medicament is then incorporated with the fluidized carboxymethyl benzyl dextran in the desired quantity and thoroughly blended by stirring and heating up to 60 C. If the medicament is solid it is generally necessary to incorporate it in solution or suspension form in order to assure thorough mixing. A preferred method is to introduce the medicament in aqueous or methanolic solution or solution in other volatile solvent from which the medicament is not readily precipitated by methanol. The fluid mass, after thorough mixing and incorporation of the medicament, is dried in vacuo at 60 C., or other temperature at which the solvents are readily removed Without undesirably affecting either the carboxymethyl benzyl dextran or medicament. After drying the mixture is crushed, preferably to pass a mesh screen and retained on a #20 mesh screen. The product can be administered in the desired dosages in either capsules or in tablet form.

The delayed release characteristics of the carboxymethyl benzyl dextran are determined by combining the carboxymethyl benzyl dextran with the medicament and then extracting the medicament with simulated gastro intestinal fluids under a standard set of conditions. The percent of the total medicament extracted during a series of specific periods of time is plotted on graph paper and the curve compared to specifications. These determinations are carried out as follows:

'One thousand milligrams of the carboxymethyl benzyl dextran medicament in granular form, prepared as above described, are dispersed in 80 ml. of simulated gastric fluid, pH 1.5 (U.S.P.) in a 250 ml. Erlenmeyer flask, which is then placed on a reciprocating shaker at 37 C. for'flve minutes. The liquid extract is then filtered through a silk screen and the residual medicament redispersed in another 80 ml. portion of gastric fluid and shaken at 37 C. for fifty-five minutes. The residual medicament from this extraction is then dispersed in simulated intestinal fluid, pH 7.5 (U.S.P.) and extracted as described above for varying periods of time. The extracts are then assayed for the medicament by any suitable means.

Example I Dextran (clinical B 512 dextran-molecular weight three million to sixty million) is dissolved and reacted in 200 mls. of water with sodium monochloroacetate, using a molar ratio of acetate to dextran of 0.5 to 1.0, the reaction being carried out at 40 C. This produces a carboxymethyl dextran having a low D.S. of carboxymethyl, which is desired for a satisfactory rate of release of the medicament, i.e., of the order of 0.15.

The sodium carboxymethyl dextran obtained as above described is then benzylated by reacting the same with benzyl chloride employing a molar ratio of benzyl chloride to sodium carboxymethyl dextran of between 3:1 and 6:1, and preferably 6:1. This produces a carboxymethyl benzyl dextran having a high benzyl D.S. (i.e., of the order of 1.5), and a low carboxymethyl D.S. (of the order of 0.15). The resultant carboxymethyl benzyl dextran is then combined with a medicament as described in Example II below. The carboxymethyl benzyl dextran used in the carboxymethyl benzyl dextran-medicament composition can be produced in various ways but preferably as follows:

Example II Sixty grams of carboxymethyl benzyl dextran as described in Example I are stirred into 300 mls. of hot C.) isopropyl alcohol and 10 grams of stearic acid. To this solution are then added 10 grams of dextroamphetamine hydrochloride while stirring the mixture. The resultant solution is then dried under vacuum at 70 C. yielding 69 grams of carboxymethyl benzyl dextroamphetamine hydrochloride. This product when tested in intestinal gastric juice at a pH of 1.3 and temperature of 37 C. was found to release between 10% and 15% of its dextroamphetamine hydrochloride content in about four hours. A quantity of 10 to 15% of dextroamphetamine hydrochloride is released in approximately eight hours when a like quantity is immersed in intestinal juice having a pH of 7.5 and temperature of 37 C. The addition of stearic acid overcomes the tendency of carboxymethyl benzyl dextran dextroamphetamine to [hydrate and agglomerate at temperatures of about 40 in aqueous media.

The amount of carboxymethyl benzyl dextran in the complex product may vary depending generally upon the medicament used. Preferably the carboxymethyl benzyl dextran content of the product is between 1 and 50% by weight of the pharmaceutical product.

To obtain the improved results it is essential to provide a carboxymethyl benzyl dextran product having a low carboxymethyl D.S. and a high benzyl D.S. The D.S. of carboxymethyl is held to 0.15 and the D.S. of benzyl to 1.5. Such a carboxymethyl benzyl dextran product has been found to release the drug slowly as desired over a prolonged period of time. The rate of release of the dextroamphetamine hydrochloride in the carboxymethyl benzyl dextran-dextroamphetamine-hydrochloride product described in controlled by the carboxymethyl benzyl dextran having the D.S. factors aforementioned. Where the D.S. factors of the carboxymethyl benzyl dextran are changed, for example, having a high D.S. of carboxymethyl and low benzyl D.S., a carboxymethyl benzyl dextran dextroamphetamine hydrochloride product made therefrom the dextroamphetamine hydrochloride is released at a more rapid rate which may be undesirable or not depending upon the dose time characteristics desired.

The invention provides a new class of dextran derivatives which can be combined with a pro-selected drug or combination of drugs to control the release of the drugs. A sustained release pharmaceutical product for introduction into the intestinal tract is provided by suitably combining a drug which is to be administered, with carboxymethyl benzyl dextran having a low carboxyalkyl D.S. and a high benzyl D.S. as aforementioned. Such a drug product, when taken orally, has a delayed releasing action, as the drug product passes through the gastro-intestinal tract, whereby the beneficial effect of the drug is extended over a much longer period of time than is otherwise possible. The carboxymethyl benzyl dextran constituent of the carboxymethyl benzyl dextran dextroamphetamine hydrochloride product described controls the rate of release of dextroamphetamine hydrochloride since the D.S. factors determine the hydratability e.g., the compatability of the carboxymethyl benzyl dextran in water and aqueous saline solutions.

Various drugs may be combined with the carboxymethyl benzyl dextran as described to form the carboxymethyl benzyl dextran-drug product having the slow release rate controlled action when taken orally or introduced into the intestinal tract.

The invention is further exemplified by the following examples:

Example Ill 25 grams (gms.) of carboxymethyl benzyl dextran (prepared as described in Example I) are dissolved in 250 mils. of hot (75 C.) methyl alcohol. To the resultant solution are added 5.3 grns. of dextroamphetamine (DA) and the solution is vacuum-dried (1 mm. Hg) for 24 hours at 70 C. Yield of 29 gms. carboxymethyl benzyl dextran dextroamphetamine product is obtained.

Example IV 50 grams of carboxymethyl benzyl dextran (Example I) are dissolved in 300 mls. of hot methyl alcohol containing gms. stearic acid and 10 gms. of dextroamphetamine hydrochloride. The resultant solution is vacuum dried for 24 hours at 70 C. to recover 70 gms. of carboxymethyl benzyl dextran dextroamphetamine hydrochloride which is pressed into pellets containing 100 mg. table ride which is pressed into pellets containing 100 mg. tablets. The incorporation of stearic acid increases the time delay about 10% over the product of Example II. Other fatty acids may be used such as those containing 10 to 24 carbon atoms.

Example V In this instance, penicillin was substituted for dextroarnphetarnine as in Example III to form a carboxymethyl benzyl dextran-penicillin product.

Example VI A carboxymethyl benzyl dextran-streptomycin complex product as in Example V is produced by substituting streptomycin for penicillin.

Example VII In this case, chloroprophenyridamine is used in place of dextroamphetamine, as in Example III, to prepare a carboxymethyl benzyl dextran-chloroprophenyridamine product.

The carboxymethyl benzyl dextran medicaments or salts of physiologically active organic bases may be prepared in any convenient dosage form. They may take the form of dry powders for use as such, to be mixed with water or a suitable liquid or non-liquid diluent to form pastes or wax-like masses, compressed into tablets, pills or pellets, or packages in dry-filled or soft elastic capsules.

The selection of the dextran to be carboxymethyl benzyl dextran may also be predicated on the particular medicament being administered. For some purposes the native dextrans, or dextrans of relatively high molecular weight, which may be more or less slowly soluble in water, are suitable. However, lower molecular weight dextrans may be used and in some cases, Water-soluble dextrans having an average molecular weight between 20,000 and desirably between 70,000 and 85,000 being most efficacious. Such water-soluble lower molecular weight dextrans may be obtained directly under predetermined and correlated conditions, or they may be obtained by hydrolysis of a high molecular weight dextran in any suitable manner, as by means of acid or enzymatically. If the dextran as obtained initially has the desired combination of physical properties, it may be carboxymethyl benzylated as described, after appropriate purification including deionization and de-colorization. If dextran is to be hydrolyzed by acid to reduce its molecular weight and render it water-soluble or increase its solubility in water this may be accomplished before or after separation of the dextran from the medium in which it is produced. Procedures for the acid hydrolysis of high molecular weight dextrans, such as that from Leuconostoc mesenteroides B-5 l2 and for fractionating the hydrolysis product to obtain so-called clinical dextran of the proper molecular weight for intravenous injection are known and may be followed.

Various changes and substitutions may be made by those skilled in the art to obtain the advantages and achieve the results of this invention and it is understood such changes and variations are within the scope of the foregoing except as restricted in the claims.

What is claimed is:

1. In the method of preparing an oral sustained release pharmaceutical product by mixing an alcoholic solution of carboxymethyl benzyl dextran and a medicament to form a complex product having sustained release properties, the irnproveemnt consisting of carrying out the method with a carboxymethyl benzyl dextran composed of benzylated water-soluble dextran of an average molecular weight between 70,000 and 85,000, the resultant carboxymethyl benzyl dextran having a low carboxymethyl D.S. of 0.15 and a high benzyl D5. of 1.5.

2. A sustained release pharmaceutical product produced in accordance with the method of claim 1.

References Cited in the file of this patent UNITED STATES PATENTS 2,989,518 Novak June 20, 196 1 3,063,905 Novak Nov. 13, 1962 3,063,906 Heckel et al. Nov. 13, 196-2 

1. IN THE METHOD OF PREPARING AN ORAL SUSTAINED RELEASE PHARMACEUTICAL PRODUCT BY MIXING AN ALCOHOLIC SOLUTION OF CARBOXYMETHYL BENZYL DEXTRAN AND A MEDICAMENT TO FORM A COMPLEX PRODUCT HAVING SUSTAINED RELEASE PROPERTIES, THE IMPROVEMENT CONSISTING OF CARRYING OUT THE METHOD WITH A CARBOXYMETHYL BENZYL DEXTRAN COMPOSED OF BENZYLATED WATER-SOLUBLE DEXTRAN OF AN AVERAGE MOLECULAR WEIGHT BETWEEN 70,000 AND 85,000, THE RESULTANT CARBOXYMETHYL BENZYL DEXTRAN HAVING A LOW CARBOXYMETHYL D.S. OF 0.15 AND A HIGH BENZYL D.S. OF 1.5. 